Ocular depressor

ABSTRACT

This invention relates to an agent for decreasing ocular tension comprising as an effective ingredient a 4,8-inter-m-phenylene PGI 2  derivative represented by the formula: ##STR1## or a pharmaceutically acceptable salt thereof. The agent for decreasing ocular tension according to the present invention is useful as a therapeutic agent for treating various high ocular tension states such as glaucoma, ocular hypertension and high ocular tension which occurs after surgery.

This application is a 371 of PCT/JP96/03351 filed on Nov. 14, 1996.

TECHNICAL FIELD

The present invention relates to an agent for decreasing ocular tension comprising as an effective ingredient a prostaglandin I₂ derivative, 4,8-inter-m-phenylene prostaglandin I₂ derivative or a salt thereof.

BACKGROUND ART

Ocular tension is adjusted by the amount of aqueous humor filling the aqueous chambers. When the production of aqueous humor is increased or excretion of aqueous humor is inhibited, the ocular tension is increased. For example, glaucoma is an ophthalmic disease in which excavatio disci nervi optici and/or visual field defect is caused by the continues high ocular tension, which leads to blindness unless the high ocular tension is well cured. Further, in a type of glaucoma, various symptoms such as visual field defect occur under the ocular tension which is considered to be physiologically normal. It is thought that this is caused by the fact that pressure sensitivity of the visual nerves of the individual is high, and the disease is called low tension glaucoma. Inversely, some individuals show abnormally high ocular tensions while no clear lesions are observed in the visual nerves. This state is called hypertonia oculi or ocular hypertension. Agents for decreasing ocular tension are useful for therapy of various high ocular tension states such as glaucoma, ocular hypertension and high ocular tension which occurs after surgery.

In recent years, it was reported that prostaglandin-related compounds have activities to decrease ocular tension (13,14-dihydro-15-keto-prostaglandins: Japanese Laid-open Patent Application (Kokai) No. 2-108; 13,14-dihydro-15(R) 17-phenyl-18,19,20-trinor prostaglandin F_(2a) ester: Japanese Laid-open Patent Application (Kokai) No. 6-500804), so that prostaglandins draw attention as drugs for decreasing ocular tension. It has been reported that prostaglandin I₂ (PGI₂, prostacyclin, Nature, Vol.268, p.688, 1976) and a derivative thereof, Iloprost (Philip F. J. Hoyng et al., 1989) have activities to decrease ocular tension in experimental animals.

However, it is known that prostaglandin I₂ and Iloprost cause transient increase in ocular tension and/or hyperemia. The object of the present invention is to provide an agent for decreasing ocular tension free from such side effects and has a high effectiveness.

PGI₂ has a drawback in that it is unstable in vivo so that its physiological activity does not last. PGI₂ derivatives with which this drawback is largely improved, which have a structure wherein the exoenol ether moiety is converted to inter-m-phenylene are described in Japanese Patent No. 1933167. It is known that these PGI₂ derivatives have a platelet aggregation-inhibition activity, vasodilating activity, gastric-acid secretion-inhibition activity, bronchodilating activity, uterine-contracting activity and the like.

DISCLOSURE OF THE INVENTION

To attain the above-mentioned object, the present invention provides a therapeutic agent for the diseases accompanied by increased ocular tension.

That is, the present invention includes the following inventions:

(1) An agent for decreasing ocular tension comprising as an effective ingredient a 4,8-inter-m-phenylene prostaglandin I₂ derivative of the formula (I): ##STR2## (wherein R¹ is (A) COOR² wherein R² is

1) hydrogen or a pharmaceutically acceptable cation,

2) C₁ -C₁₂ straight alkyl or C₃ -C₁₄ branched alkyl,

3) --Z--R³

wherein Z is valence bond or straight or branched alkylene represented by C_(t) H_(2t) wherein t is an integer of 1-6; R³ is a C₃ -C₁₂ cycloalkyl or a C₃ -C₁₂ substituted cycloalkyl substituted with 1-3 R⁴ groups, wherein R⁴ is hydrogen or C₁ -C₅ alkyl,

4) --(CH₂ CH₂ O)_(n) CH₃

wherein n is an integer of 1-5,

5) --Z--Ar¹

wherein Z represents the same meaning as described above, Ar¹ is phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl (wherein substituent is at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, --CH═N--NH--C(═O)--NH₂, --NH--C(═O)--Ph, --NH--C(═O)--CH₃ or --NH--C(═O)--NH₂),

6) --C_(t) H_(2t) COOR

wherein C_(t) H_(2t) and R⁴ represent the same meanings as described above,

7) --C_(t) H_(2t) N(R⁴)₂

wherein C_(t) H_(2t) and R⁴ represent the same meanings as described above,

8) --CH(R⁵)--C(═O)--R⁶

wherein R⁵ is hydrogen or benzoyl, R⁶ is phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl, 2-naphthyl,

9) --C_(P) H_(2P) --W--R⁷

wherein W is --CH═CH--, --CH═CR⁷ -- or --C.tbd.C--; R⁷ is hydrogen or C₁ -C₃₀ straight or branched alkyl or aralkyl; and p is an integer of 1-5, or

10) --CH(CH₂ OR⁸)₂

wherein R⁸ is C₁ -C₃₀ alkyl or acyl,

(B) --CH₂ OH

(C) --C(═O)N(R⁹)₂

wherein R⁹ is hydrogen, C₁ -C₁₂ straight alkyl, C₃ -C₁₂ branched alkyl, C₃ -C₁₂ cycloalkyl, C₄ -C₁₃ cycloalkylalkylene, phenyl, substituted phenyl (wherein substituents are the same as the substituents as in (A)5)) C₇ -C₁₂ aralkyl or --SO₂ R¹⁰ wherein R¹⁰ is C₁ -C₁₀ alkyl, C₃ -C₁₂ cycloalkyl, phenyl, substituted phenyl (wherein substituents are the same as the substituents as in (A)5)) or C₇ -C₁₂ aralkyl, with the proviso that although the two R⁹ groups may be the same or different, in cases where one of them is --SO₂ R¹⁰, the other is not --SO₂ R¹⁰, or

(D) --CH₂ OTHP (wherein THP is tetrahydropyranyl group),

A is

1) --(CH₂)_(m) --

2) --CH═CH--CH₂ --

3) --CH₂ --CH═CH--

4) --CH₂ --O--CH₂ --

5) --CH═CH--

6) --O--CH₂ -- or

7) --CH.tbd.C--

wherein m is an integer of 1 or 2,

Y is hydrogen, C₁ -C₄ alkyl, chlorine, bromine, fluorine, formyl, methoxy or nitro,

B is

--X--C(R¹¹) (R¹²)OR¹³

wherein R¹¹ is hydrogen or C₁ -C₄ alkyl, R¹³ is hydrogen, C₁ -C₁₄ acyl, C₆ -C₁₅ aroyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl,

X is

1) --CH₂ --CH₂ --

2) --CH═CH-- or

3) --C.tbd.C--

R¹² is

1) C₁ -C₁₂ straight alkyl, C₃ -C₁₄ branched alkyl or

2) --Z--Ar²

wherein Z represents the same meaning as described above, Ar² is phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, or

3) --C_(t) H_(2t) OR¹⁴

wherein C_(t) H_(2t) represents the same meaning as described above, R¹⁴ is C₁ -C₆ straight alkyl, C₃ -C₆ branched alkyl, phenyl, at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1-4 C₁ -C₄ straight alkyl groups, or

4) --Z--R³

wherein Z and R³ represent the same meanings as described above,

5) --C_(t) H_(2t) --CH═C(R¹⁵ )R¹⁶

wherein C_(t) H_(2t) represents the same meaning as described above, R¹⁵ and R¹⁶ are hydrogen, methyl, ethyl, propyl or butyl, or

6) --C_(u) H_(2u) --C.tbd.C--R¹⁷

wherein u is an integer of 1-7, C_(u) H_(2u) is straight or branched alkylene and R¹⁷ is C₁ -C₆ straight alkyl,

E is hydrogen or --OR¹⁸

wherein R¹⁸ is C₁ -C₁₂ acyl, C₇ -C₁₅ aroyl or R²

(wherein R² represents the same meaning as described above)

the formula (I) including d-isomer, l-isomer and dl-isomer)

or a pharmaceutically acceptable salt thereof.

(2) An agent for decreasing ocular tension comprising as an effective ingredient the compound recited in (1) or a pharmaceutically acceptable salt thereof, wherein

R¹ is

(A) COOR²

wherein R² is

1) hydrogen or a pharmaceutically acceptable cation,

2) C₁ -C₁₂ straight alkyl or C₃ -C₁₄ branched alkyl, or

(B) --CH₂ OH

A is

1) --(CH₂)_(m) --

2) --CH═CH-- or

3) --O--CH₂ --

wherein m is an integer of 1 or 2,

Y is hydrogen,

B is

--X--C(R¹¹)(R¹²)OR⁻⁻

wherein R¹¹ is hydrogen and R¹³ is hydrogen,

X is

1) --CH₂ --CH₂ -- or

2) --CH═CH--

R¹² is

1) C₁ -C₁₂ straight alkyl, C₃ -C₁₄ branched alkyl, or

2) --Z--Ar²

wherein Z represents the same meaning as described above, Ar² is phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, or

3) --C_(t) H_(2t) OR¹⁴

wherein C_(t) H_(2t) represents the same meaning as described above, R¹⁴ is C₁ -C₆ straight alkyl, C₃ -C₆ branched alkyl, phenyl, at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1-4 C₁ -C₄ straight alkyl groups, or

4) --C_(u) H_(2u) --C.tbd.C--R¹⁷

wherein u is an integer of 1-7, C_(u) H_(2u) is straight or branched alkylene, and R¹⁷ represents C₁ -C₆ straight alkyl, and

E is OH.

(3) The agent for decreasing ocular tension according to (1), wherein the disease accompanied by increased ocular tension is glaucoma, ocular hypertension or high ocular tension which occurs after surgery.

(4) A formulation comprising the compound recited in (1) and one or more other drugs having an ocular tension-decreasing activity.

(5) Use of the compound recited in (1) as a therapeutic agent for diseases accompanied by increased ocular tension.

(6) Use of the compound recited in (1) by administering the compound to a patient suffering from a disease accompanied by increased ocular tension.

(7) A method for treating a patient suffering from a disease accompanied by increased ocular tension, comprising administering to the patient the compound recited in (1).

The agent for decreasing ocular tension according to the present invention is useful for therapy of various high ocular tension states in glaucoma, ocular hypertension, high ocular tension which occurs after surgery or the like.

In cases where the compound according to the present invention is administered in the form of an eye drop, the compound is formulated into a solution with a concentration of usually 0.0001-0.5%, preferably 0.001 -0.1%.

In cases where the agent for decreasing ocular tension according to the present invention is used in the form of eye drop, additives which are usually blended to eye drops may be added as required as long as they do not adversely affect the effect of the present invention. Usually, as the additives, buffers such as phosphate buffer; isotonizing agents such as sodium chloride and concentrated glycerin; antiseptics such as benzalkonium chloride; solubilizers (stabilizers) such as cyclodextrin; surfactants such as polysorbate 80; pH regulators such as sodium phosphate; thickeners such as carboxymethyl cellulose; chelating agents such as disodium edetate; and the like are used.

Since the agent for decreasing ocular tension according to the present invention has a stable chemical structure, there is no difficulties in formulating the compound. Therefore, in addition to the eye drop mentioned above, the compound may be formulated into an oral drug, injection solution, absorbefacient, external formulation such as ointment, and a suppository.

The formulation of the agent for decreasing ocular tension according to the present invention may contain another drug having an activity to decrease ocular tension. As the drug having an activity to decrease ocular tension, sympathomimetic such as epinephrine; sympathicolytic drugs such as timolol, parasympathomimetics such as pilocarpine; prostaglandin compounds such as isopropyl unoprostone; and the like are used.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the ocular tension-decreasing action of the compound according to the present invention; and

FIG. 2 is a graph showing the ocular tension-decreasing action of PGI₂.

BEST MODE FOR CARRYING OUT THE INVENTION

The ocular tension-decreasing action of the compounds of the above-described formula (I) will now be described concretely by way of examples. It should be noted, however, the present invention is not limited to the examples.

EXAMPLE 1 Ocular Tension-Decreasing Action

Using groups of New Zealand White rabbits having body weights of 2-4 kg, the ocular tension-decreasing action of the compounds of the formula (I) was tested, each group consisting of 2 or 3 rabbits. The compounds shown in Table 1 below were used as the test compounds. Further, for comparison, the action of PGI₂ was also tested.

To one eye, 30 μl of the test drug was administered and 30 μl of a solvent was administered to the other eye. The ocular tensions at 30 minutes to 6 hours after the administration were measured with ALCON APPLANATION PNEUMATONGRAPH electronic tonometer (ALCON JAPAN CO., LTD). When measuring the ocular tensions, 4% oxyprocaine was administered as a surface anesthetic. The test drugs were dissolved in the solvents shown in Tables 2 and 3.

FIG. 1 shows the change in ocular tension after administration of Compound 1 with time. Compound 1 decreased the ocular tension at the concentration of 0.01% and its maximum value was 7.3 mmHg. During this test, Compound 1 did not bring about the transient increase in ocular tension or hyperemia unlike the naturally occurring prostaglandins (Table 2). FIG. 2 shows the change in ocular tension after administration of PGI₂ with time. PGI₂ did not show ocular tension-decreasing action even at the concentration of 0.1%, and only hyperemia-causing action was observed (Table 2).

In Table 3, the ocular tension-decreasing actions of the compounds of the present invention shown in Table 1 other than Compound 1 are shown.

                  TABLE 1                                                          ______________________________________                                         Compound 1                                                                               A      --(CH.sub.2).sub.2 --                                            R.sup.1 --COCNa                                                                Y --H                                                                          -  B                                                                                           #STR3##                                                        -  E                                                                                           #STR4##                                                        - Compound 2 A --(CH.sub.2).sub.2 --                                           R.sup.1 ----COOCH.sub.3                                                        Y --H                                                                          -  B                                                                                           #STR5##                                                        -  E                                                                                           #STR6##                                                        - Compound 3 A --(CH.sub.2).sub.2 --                                           R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR7##                                                        -  E                                                                                           #STR8##                                                        - Compound 4 A --O--CH.sub.2 --                                                R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR9##                                                        -  E                                                                                           #STR10##                                                       - Compound 5 A --O--CH.sub.2 --                                                R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR11##                                                       -  E                                                                                           #STR12##                                                       - Compound 6 A --(CH.sub.2).sub.2 --                                           R.sup.1 --CH.sub.2 OH                                                          Y --H                                                                          -  B                                                                                           #STR13##                                                       -  E                                                                                           #STR14##                                                       - Compound 7 A --(CH.sub.2).sub.2 --                                           R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR15##                                                       -  E                                                                                           #STR16##                                                       - Compound 8 A --O--CH.sub.2 --                                                R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR17##                                                       -  E                                                                                           #STR18##                                                       - Compound 9 A --(CH.sub.2).sub.2 --                                           R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR19##                                                       -  E                                                                                           #STR20##                                                       - Compound 10 A --CH═CH--                                                  R.sup.1 --CH.sub.2 OH                                                          Y --H                                                                          -  B                                                                                           #STR21##                                                       -  E                                                                                           #STR22##                                                       - Compound 11 A --O--CH.sub.2 --                                               R.sup.1 --COOH                                                                 Y --H                                                                          -  B                                                                                           #STR23##                                                       -  E                                                                                          ##STR24##                                                    ______________________________________                                    

                  TABLE 2                                                          ______________________________________                                                                        Number of                                           Concen- Animals Which                                                        Compound Solvent tration Showed Hyperemia                                    ______________________________________                                         Compound 1                                                                             100 mM phosphate                                                                             0.01%    0                                                  buffer                                                                        PGI.sub.2 100 mM carbonate 0.1%  3                                              buffer                                                                      ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                                                           Maximum                                           Decrease                                                                       in Ocular                                                                   Test  Concen- Tension                                                          Compound Solvent tration (mmHg)                                              ______________________________________                                         Compound 2  2% polysorbate 80                                                                            0.001   5.9                                            Compound 3 100 mM phosphate 0.1 4.1                                             buffer                                                                        Compound 4 100 mM phosphate 0.001 6.4                                           buffer                                                                        Compound 5 100 mM phosphate 0.01 6.7                                            buffer                                                                        Compound 6 2% polysorbate 80 0.01 5.9                                          Compound 7 100 mM phosphate 0.01 1.1                                            buffer                                                                        Compound 8 100 mM phosphate 0.01 2.6                                            buffer                                                                        Compound 9 100 mM phosphate 0.01 4.2                                            buffer                                                                        Compound 10 2% polysorbate 80 0.01 3.6                                         Compound 11 100 mM phosphate 0.01 2.7                                           buffer                                                                      ______________________________________                                    

Industrial Availability

The 4,8-inter-m-phenylene prostaglandin I₂ derivatives according to the present invention have excellent pharmacological effects and do not cause transient increase in ocular tension and/or hyperemia, so that they are useful as the agents for decreasing ocular tension. 

What is claimed is:
 1. A method for treating a patient suffering from a disease accompanied by increased ocular tension, comprising administering to the patient a therapeutically effective amount of a 4,8-inter-m-phenylene prostaglandin I₂ derivative of the following formula (I): ##STR25## (wherein R¹ is (A) COOR² wherein R² is1) hydrogen or a pharmaceutically acceptable cation, 2) C₁ -C₁₂ straight alkyl or C₃ -C₁₄ branched alkyl, 3) --Z--R³ wherein Z is valence bond or straight or branched alkylene represented by C_(t) H_(2t) wherein t is an integer of 1-6; R³ is a C₃ -C₁₂ cycloalkyl or a C₃ -C₁₂ substituted cycloalkyl substituted with 1-3 R⁴ groups, wherein R⁴ is hydrogen or C₁ -C₅ alkyl, 4) --(CH₂ CH₂ O)_(n) CH₃ wherein n is an integer of 1-5, 5) --Z--Ar¹ wherein Z represents the same meaning as described above, Ar¹ is phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl (wherein substituent is at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, --CH═N--NH--C(═O)--NH₂, --NH--C(═O)--Ph, --NH--C(═O)--CH₃ or --NH--C(═O)--NH₂), 6) --C_(t) H_(2t) COOR⁴ wherein C_(t) H_(2t) and R⁴ represent the same meanings as described above, 7) --C_(t) H_(2t) N(R⁴)₂ wherein C_(t) H_(2t) and R⁴ represent the same meanings as described above, 8) --CH(R⁵)--C(═O)--R⁶ wherein R⁵ is hydrogen or benzoyl, R⁶ is phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl, 2-naphthyl, 9) --C_(P) H_(2P) --W--R⁷ wherein W is --CH═CH--, --CH═CR⁷ -- or --C.tbd.C--; R⁷ is hydrogen or C₁ -C₃₀ straight or branched alkyl or aralkyl; and p is an integer of 1-5, or 10) --CH(CH₂ OR⁸ )₂ wherein R⁸ is C₁ -C₃₀ alkyl or acyl, (B) --CH₂ OH (C) --C(═O)N(R⁹)₂ wherein R⁹ is hydrogen, C₁ -C₁₂ straight alkyl, C₃ -C₁₂ branched alkyl, C₃ -C₁₂ cycloalkyl, C₄ -C₁₃ cycloalkylalkylene, phenyl, substituted phenyl (wherein substituents are the same as the substituents as in (A)5)), C₇ -C₁₂ aralkyl or --SO₂ R¹⁰ wherein R¹⁰ is C₁ -C₁₀ alkyl, C₃ -C₁₂ cycloalkyl, phenyl, substituted phenyl (wherein substituents are the same as the substituents as in (A)5)) or C₇ -C₁₂ aralkyl, with the proviso that although the two R⁹ groups may be the same or different, in cases where one of them is --SO₂ R¹⁰, the other is not --SO₂ R¹⁰, or (D) --CH₂ OTHP (wherein THP is tetrahydropyranyl group), A is1) --(CH₂)_(m) -- 2) --CH═CH--CH₂ -- 3) --CH₂ --CH═CH-- 4) --CH₂ --O--CH₂ -- 5) --CH═CH-- 6) --O--CH₂ -- or 7) --C.tbd.C--wherein m is an integer of 1 or 2, Y is hydrogen, C₁ -C₄ alkyl, chlorine, bromine, fluorine, formyl, methoxy or nitro, B is--X--C(R¹¹)(R¹²)OR¹³ wherein R¹¹ is hydrogen or C₁ -C₄ alkyl, R¹³ is hydrogen, C₁ -C₁₄ acyl, C₆ -C₁₅ aroyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl, X is1) --CH₂ --CH₂ -- 2) --CH═CH-- or 3) --C.tbd.C-- R¹² is1) C₁ -C₁₂ straight alkyl, C₃ -C₁₄ branched alkyl or 2) --Z--Ar² wherein Z represents the same meaning as described above, Ar² is phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, or 3) --C_(t) H_(2t) OR¹⁴ wherein C_(t) H_(2t) represents the same meaning as described above, R¹⁴ is C₁ -C₆ straight alkyl, C₃ -C₆ branched alkyl, phenyl, at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1-4 C₁ -C₄ straight alkyl groups, or 4) --Z--R³ wherein Z and R³ represent the same meanings as described above, 5) --C_(t) H_(2t) --CH═C(R¹⁵)R¹⁶ wherein --C_(t) H_(2t) represents the same meaning as described above, R¹⁵ and R¹⁶ are hydrogen, methyl, ethyl, propyl or butyl, or 6) --C_(u) H_(2u) --C.tbd.C--R¹⁷ wherein u is an integer of 1-7, C_(u) H_(2u) is straight or branched alkylene and R¹⁷ is C₁ -C₆ straight alkyl, E is hydrogen or --OR¹⁸ wherein R¹⁸ is C₁ -C₁₂ acyl, C₇ -C₁₅ aroyl or R² (wherein R² represents the same meaning as described above) the formula (I) including d-isomer, l-isomer and dl-isomer) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 2. The method according to claim 1, wherein said disease accompanied by increased ocular tension is glaucoma, ocular hypertension or high ocular tension that occurs after surgery.
 3. The method according to claim 1, wherein in formula (I),R¹ is(A) COOR² wherein R² is 1) hydrogen or a pharmaceutically acceptable cation, 2) C₁ -C₁₂ straight alkyl or C₃ -C₁₄ branched alkyl, or (B) --CH₂ OH A is1) --(CH₂)_(m) -- 2) --CH═CH-- or 3) --O--CH₂ --wherein m is an integer of 1 or 2, Y is hydrogen, B is--X--C(R¹¹)(R¹²)OR¹³ wherein R¹² is hydrogen and R¹³ is hydrogen, X is1) --CH₂ --CH₂ -- or 2) --CH═CH-- R¹² is1) C₁ -C₁₂ straight alkyl, C₃ -C₁₄ branched alkyl, or 2) --Z--Ar² wherein Z represents the same meaning as described above, Ar² is phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, or 3) --C_(t) H_(2t) OR¹⁴ wherein C_(t) H_(2t) represents the same meaning as described above, R¹⁴ is C₁ -C₆ straight alkyl, C₃ -C₆ branched alkyl, phenyl, at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, C₁ -C₄ alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1-4 C₁ -C₄ straight alkyl groups, or 4) --C_(u) H_(2u) --C.tbd.C--R¹⁷ wherein u is an integer of 1-7, C_(u) H_(2u) is straight or branched alkylene, and R¹⁷ represents C₁ -C₆ straight alkyl, and E is OH. 